Substituted N-benzylpiperidine amides

ABSTRACT

Substituted N-benzylpiperidine amides, which have activity as Class III antiarrhythmic agents, acting by prolonging cardiac action potential repolarization. The invention further provides for compositions incorporating the compunds and methods of their use, as well as providing for pharmaceutically acceptable salts of the compounds.

BACKGROUND OF THE INVENTION

The present invention provides novel compounds, novel compositions,methods of their use and methods of their manufacture, such compoundspharmacologically useful in the treatment of cardiac arrhythmias. Morespecifically, the compounds of the present invention are Class IIIantiarrhythmic agents which, by effectively prolonging repolarization ofa cardiac cell action potential, can be used effectively to treatcertain cardiac arrhythmias.

Antiarrhythmic drugs have been grouped together according to the patternof electrophysiological effects that they produce and/or their presumedmechanisms of action. Thus, Class I antiarrhythmic agents arecharacterized by being sodium channel blockers, Class II antiarrhythmicagents are beta adrenergic blockers, Class III antiarrhythmic agentsprolong repolarization, and Class IV antiarrhythmic agents are calciumchannel blockers.

Currently, there are very few Class III antiarrhythmic agents availablefor therapeutic use. Among them is bretylium. Bretylium's usefulness islimited, however, and currently its theraputic use is reserved forlife-threatening ventricular arrhythmias that are refractory to othertherapy. Thus, bretylium's use is generally confined to intensive careunits. It is an object of this invention to provide Class IIIantiarrhythmic agents of broader theraputic use than existing Class IIIantiarrhythmic agents.

SUMMARY OF THE INVENTION

The invention relates to novel compounds of the general formula I:##STR1## the pharmaceutically acceptable non toxic salts thereof and thehydrated forms thereof,

wherein R¹ is alkyl, alkenyl or alkynyl of from one to ten carbon atoms;substituted or unsubstituted aralkyl, aralkenyl or aralkynyl of from oneto ten carbon atoms and wherein said aryl substituent is one or more ofalkoxy, nitro, halogen or alkylsulfonamide at any position with alkoxyor alkylsulfonamide having alkyl, alkenyl or alkynyl of one to tencarbon atoms; alkyl, alkenyl or alkynyl of from one to ten carbon atomssubstituted by furanyl, imidazolyl, pyridinyl, or imidazolyl substitutedby alkoxycarbonyl having alkyl, alkenyl or alkynyl of one to ten carbonatoms; arylamino; substituted aryl, unsubstituted aryl or either of themfused to substituted or unsubstituted cycloalkyl of from three to eightcarbon atoms wherein said cycloalkyl substituent can be halogen;unsubstituted cycloalkyl of from three to eight carbon atomsarylcyloalkyl wherein cycloalkyl is from three to eight carbon atoms;pyridinyl; furanyl; halogen substituted furanyl; substituted orunsubstituted benzofuranyl wherein said benzofuranyl substituent can beone or more at any position of halogen, amino, nitro or alkoxy havingalkyl, alkenyl or alkynyl of from one to ten carbon atoms; substitutedor unsubstituted benzopyranyl wherein said substituent can be keto;thiophene; benzothiophene; or substituted or unsubstituted indene orisoindene wherein said substituent is alkyl of one to ten carbon atoms;

n is an integer of from one to ten;

R² is unsubstituted or is alkyl, alkenyl or alkynyl of from one to tencarbon atoms or oxygen that is present as an N-oxide; R³ is hydrogen,carboxyalkyl, carboxy alkenyl or carboxy alkynyl of from one to tencarbon atoms or alkoxycarbonylalkyl, alkoxycarbonylalkenyl oralkoxycarbonylalkynyl and wherein the alkoxy moiety can have alkyl,alkenyl or alkynyl of from one to ten carbon atoms; ##STR2## ishydrogen; pyridinyl; cycloalkyl of three to eight carbon atoms orhydroxy substituted cycloalkyl of three to eight carbon atoms; furanyl;or unsubstituted or substituted phenyl wherein said phenyl substituentis one or more of alkyl or halogen substituted alkyl of one to tencarbon atoms, alkoxy from one to ten carbon atoms, nitro, amine, mono ordi alkylamine, acetyl amine, acetylamide, halogen or alkoxy itselfsubstituted by halogen substituted phenyl; and R⁴ is alkoxycarbonyl offrom one to ten carbon atoms.

The compounds and pharmaceutical compositions thereof are useful in theantiarrhythmic methods of the invention. The invention further providesdosage unit forms adapted for oral, topical and parenteraladministration. Also provided for in this invention are thepharmaceutically acceptable salts of the compounds.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" shall mean straight or branched chaincarbon-carbon linkages of from one to ten carbon atoms. "Alkenyl" shallhave the same meaning, except that one or more double bonds may bepresent therein. "Alkynyl" shall have the same meaning, except that oneor more triple bonds may be present therein.

"Alkoxy" shall include alkyl, alkenyl and alkynyl, as defined above,substituted by an epoxide oxygen.

"Aralkyl" shall include alkyl, alkenyl and alkynyl, as defined above,substituted by an aryl group, which is defined below.

"Aryl" shall mean phenyl.

"Halogen" shall include fluorine, chlorine, bromine or iodine.

The term "cardiac arrhythmia" is defined to mean any variation from thenormal rhythm of the heartbeat, including, without limitation, sinusarrhythmia, premature heartbeat, heartblock, fibrillation, flutter,pulsus alternans, tachycardia, paroxysmal tachycardia and prematureventricular contractions.

The term "repolarization of cardiac cells" is defined as those phases ofa cardiac action potential during which time a depolarized cardiac cellis reverting to normal pre-polarization transmembrane voltage.

The term "pharmaceutically acceptable salts" refers to non-toxic saltsof the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts include the hydrochloride, hydroiodic,hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate,clavulanate, methaneperoxoate and the like salts.

Compounds of the invention can be prepared readily according to thefollowing reaction scheme or modifications thereof using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are in themselves known, but are not mentioned in greaterdetail. R¹, R², R³ and ##STR3## are as defined above. Y is any suitableleaving group, such as halogen, mesylate or tosylate. COZ represents asuitable acylating agent such as a carboxylic acid chloride, acarboxylic acid activated as the mixed anydride, or the carboxylic esteractivated by alkylaluminum reagents. ##STR4##

Reduction of 4-acetamidopyridine Formula II affords4-acetamido-piperidine Formula III. A method for the preparation of4-acetamidopiperidine III involves the reduction of 4-acylamino N-benzylpyridinium compounds by alkali metal hydrides or catalytic hydrogenationof the aromatic ring with debenzylation as described in U.K. 1,537,867(G. O. Weston) and U.K. 1,345,872 (J. L. Archibald and J. F. Cavalla)the disclosures of which are incorporated herein by reference. Preferredreduction conditions employ a ruthenium on carbon catalyst in a solventsuch as alcohol, tetra hydrofuran, (THF), or acetic acid under anatmosphere of hydrogen. Subsequent reductive alkylation of thepiperidine Formula III with aldehydes Formula IV provides theN-alkylated intermediates Formula V. Preferred conditions employ Pt/Ccatalyst in an inert solvent such as alcohol, THF, or acetic acid underan atmosphere of hydrogen. Alternative preferred conditions employborane-pyridine complex as the reducing agent at room temperature inalcohol, acetic acid or methylene chloride. Hydrolysis of the amide bondof acetamides Formula V provides amine intermediates Formula VI.Although hydrolysis may be effected in acid or base, the preferredmethod employs hydrolysis in 1.2 M HCl at 100° C. Alternative preferredacylating conditions leading to amides I (R² =lone pair) employ COZ,which can be a carboxylic acid chloride, a carboxylic acid activated asthe mixed anhydride, or the carboxylic ester activated by alkylaluminumreagents.

The intermediates Formula I are subsequently converted to the quaternarysalts Formula I (where R² is not an unshared valence bond) byN-alkylating reagents R² X Formula VIII (where X is a suitable leavinggroup such as halogen, mesylate, or tosylate) in an inert solvent.Preferred alkylation conditions employ acetonitrile as the solvent atroom temperature.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules, pills, powders, granules, elixers,tinctures, suspensions, syrups and emulsions. Likewise, it can also beadministered in intravenous, intraperitoneal, subcutaneous orintramuscular form, all using forms known to those of ordinary skill inthe pharmaceutical arts. In general, the preferred form ofadministration is oral. An effective but non-toxic amount of thecompound is employed in the treatment of arrhythmias of the heart. Thedosage regimen utilizing the compound of the present invention isselected in accordance with a variety of factors including the type,species, age, weight, sex and medical condition of the patient; with theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound employed or salt thereof. An ordinarily skilled veterinarian orphysician can readily determine and prescribe the effective amount ofthe drug required to prevent, treat or arrest the progress of thecondition.

Oral dosages of the compounds of the present invention, when used forthe indicated cardiac effects, will range between about 0.1 mg perkilogram of body weight per day (mg/kg/day) to about 1000 mg/kg/day andpreferably 1.0 to 100 mg/kg/day. Advantageously, the compounds of thepresent invention can be administered in a single daily dose or thetotal daily dosage can be administered in divided doses of two, three orfour times daily.

In the pharmaceutical compositions and methods of the present invention,the compounds described in detail below will form the active ingredientthat will typically be administered in admixture with suitablepharmaceutical diluents, excipients or carriers (collectively referredto herein as "carrier" materials) suitably selected with respect to theintended form of administration, that is, oral tablets, capsules,elixers, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of tablets orcapsules, the active drug component can be combined with an oralnon-toxic pharmaceutically acceptable inert carrier such as lactose,starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol and the like; for oraladministration in liquid form, the active drug components can becombined with any oral non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. In the case oforal administration and in liquid form, suitable flavoring carriers canbe added such as cherry syrup and the like. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents andcoloring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol and various waxes. Lubricants for use in thesedosage forms include magnesium stearate, sodium benzoate, sodiumacetate, sodium stearate, sodium chloride, sodium oleate and the like.Disintegrators include, without limitation, starch, methylcellulose,agar, bentonite, xanthan gum and the like.

The compounds of this invention can also be administered by intravenousroute in doses ranging from 0.01 to 10 mg/kg/day.

Furthermore, it is also contemplated that the invention can beadministered in an intranasal form topically via the use of suitableintranasal vehicles, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in thatart. In the case of transdermal skin patch administration, daily dosageis continuous via the transdermal delivery system rather than divided,as in an oral delivery system.

The compounds of this invention exhibit antiarrythmic activity useful inthe treatment of various cardiac arrhythmias. The test proceduresemployed to measure this activity of the compounds of the presentinvention are described below.

EXAMPLE 1

Guinea pigs, of either sex weighing between 200-350 g, are acutelysacrificed and the right ventricular papillary muscle is isolated. Asample of a given test compound is added using an in vitro tissue bath.Concentrations used are generally 3×10⁻⁵ M, but may also be as low as3×10⁻⁷ M. Changes in refractory period are measured before and afteradding 1 concentration (usually 3×10⁻⁵ M, as noted above) of a testcompound to the bath. One hour is allowed for drug equilibration. Acompound is considered active (Class III) if an increase in ventricularrefractory period is 25 msec or more (at 3×10⁻⁵ M).

    ______________________________________                                                    Results                                                           Compound    Concentration (M)                                                                           Change (msec)                                       ______________________________________                                        H.sub.2 O   --             8                                                  Disopyramide                                                                              3 × 10.sup.-5                                                                         20                                                  Clofinium   3 × 10.sup.-5                                                                         24                                                  Sotalol     3 × 10.sup.-5                                                                         35                                                  Example 9   3 × 10.sup.-5                                                                         55                                                  Example 10  3 × 10.sup.-5                                                                         50                                                  Example 11  3 × 10.sup.-5                                                                         30                                                  Example 12  1 × 10.sup.-6                                                                         20                                                  Example 13  3 × 10.sup.-5                                                                         40                                                  Example 14  1 × 10.sup.-6                                                                         15                                                  Example 15  3 × 10.sup.-5                                                                         40                                                  Example 16  1 × 10.sup.-6                                                                         30                                                  Example 17  3 × 10.sup.-5                                                                         30                                                  Example 18  3 × 10.sup.-5                                                                         55                                                  Example 19  1 × 10.sup.-6                                                                         25                                                  Example 20  1 × 10.sup.-6                                                                         40                                                  Example 21  3 × 10.sup.-5                                                                         190                                                 Example 22  3 × 10.sup.-5                                                                         95                                                  Example 23  3 × 10.sup.-5                                                                         35                                                  Example 24  3 × 10.sup.-5                                                                         60                                                  Example 25  3 × 10.sup. -5                                                                        60                                                  Example 26  3 × 10.sup.-5                                                                         90                                                  Example 29  3 × 10.sup.-6                                                                         60                                                  Example 87  3 × 10.sup.-6                                                                         55                                                  Example 30  3 × 10.sup.-6                                                                         80                                                  Example 36  3 × 10.sup.-6                                                                         55                                                  Example 37  3 × 10.sup.-5                                                                         35                                                  Example 39  3 × 10.sup.-5                                                                         155                                                 Example 40  3 × 10.sup.-5                                                                         125                                                 Example 41  3 × 10.sup.-6                                                                         70                                                  Example 42  3 × 10.sup.-6                                                                         60                                                  Example 44  3 × 10.sup.-6                                                                         40                                                  Example 46  3 × 10.sup.-6                                                                         95                                                  Example 51  3 × 10.sup.-6                                                                         75                                                  Example 53  3 × 10.sup.-6                                                                         50                                                  Example 58  3 × 10.sup.-6                                                                         60                                                  Example 59  3 × 10.sup.-6                                                                         35                                                  Example 60  3 × 10.sup.-6                                                                         25                                                  Example 64  3 × 10.sup.-5                                                                         85                                                  Example 66  3 × 10.sup.-5                                                                         45                                                  Example 69  3 × 10.sup.-5                                                                         25                                                  Example 70  3 × 10.sup.-5                                                                         40                                                  Example 72  3 × 10.sup. -5                                                                        50                                                  Example 75  3 × 10.sup.-5                                                                         60                                                  Example 77  1 × 10.sup.-6                                                                         60                                                  Example 78  3 × 10.sup.-6                                                                         50                                                  Example 80  3 × 10.sup.-5                                                                         115                                                 Example 82  3 × 10.sup.-6                                                                         55                                                  ______________________________________                                    

The preferred compounds of the invention are any or all of thosespecifically set forth below. The compounds are not, however, to beconstrued as forming the only genus that is considered as the inventionand any combination of such compounds may itself form a genus orsub-genus. ##STR5##

The following non-limiting examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted. Melting points were determined on a Thomas-HooverUnimelt Capillary Apparatus and are not corrected. Unless otherwisenoted, I.R. and NMR spectra were consistent with the assigned structure.

EXAMPLE 2 ##STR6## Preparation of 4-acetamidopyridine acetate II

4-Aminopyridine (101.28 g) and acetic anhydride (110 g) were mixed neatand heated at 100° C. for 1/2 h. The solidified reaction mixture wastriturated with acetone, filtered off, and washed with ether to afford186.48 g of II as a white solid in two crops. Anal. calcd for C₉ H₁₂ N₂O₃ : C, 55.09; H, 6.16; N, 14.26. Found: C, 55.04; H, 5.96; N, 15.22.

EXAMPLE 3 ##STR7## Preparation of 4-acetamidopiperidine acetate III

A solution of the product of Example 2 (75 g) in 750 mL acetic acid wasreduced over PtO₂ catalyst at 60 psi hydrogen atmosphere at 60° C. for 7hours. The solution was filtered, concentrated and triturated with etherto afford the title compound quantitatively as a white solid which wasused directly in subsequent reactions.

EXAMPLE 4 ##STR8## Preparation of1-(4-methoxyphenyl)methyl-4-acetamido-piperidine

A mixture of 10 g amine acetate from Example 3 and 13.48 g 4-methoxybenzaldehyde was hydrogenated in 100 mL ethanol over a Pt/C catalyst atroom temperature for 3 hours. The reaction mixture was filtered andconcentrated to give 74.0 g of the acetate salt of the title compound asa white solid which was hydrolyzed directly as described in Example 4.(An alternative reductive amination procedure is described in Example5). Conversion of a sample to the free base using aqueous base and ethylacetate extraction provided a white solid after solvent evaporation andtrituration with ether: mp 140°-142° C.; Anal. calcd for C₁₅ H₂₂ N₂ O₂ :C, 68.67; H, 8.45; N, 10.68. Found: C, 65.26; H, 8.60; N, 10.77.

EXAMPLE 5 ##STR9## Preparation of 1-(4-methoxyphenyl)methyl-4-aminopiperidine

A) A solution of 50 g of the product of Example 4 was dissolved in 500mL of 1.2N HCl and heated at 100° C. for 8 h. The solution was madealkaline with 50% aq. NaOH and extracted three times with ether. Thecombined organic layers were washed with water and saturated brine,dried over sodium sulfate, and concentrated to give the title compoundas 28 g of clear oil which was used without further purification.

B) (Alternative general reductive alkylation procedure) A solution of 50mmol amine acetate (product of Example 3) and 100 mmol of4-methoxybenzaldehyde in 125 mL methylene chloride and 15 mL acetic acidwas treated with 50 mmol of borane-pyridine complex and allowed to stirat room temperature overnight. The removal of volatiles by rotaryevaporation afforded the acetamide of Example 4 as an oil which wasdissolved in 300 mL of 1.2N HCl and heated overnight on a steam bath.The cooled reaction mixture was extracted once with a 50 mL portion ofethyl acetate which was discarded. The aqueous layer was made basic withaq. NaOH and extracted three times with 50 mL ether. The combined layerswere washed with water and dried over sodium sulfate. Solvent removalafforded the title compound as a crude oil (yield typically 60-70% fortwo steps) which was used directly without further purification.

EXAMPLE 6 General acylation procedures

A) 10 mmol of the amine of Example 5 is dissolved in a mixture of 25 mLchloroform and 11 mmol of triethylamine cooled to 0° C. A solution of 11mmol of the acyl chloride neat or dissolved in 25 mL chloroform is addeddropwise and the reaction mixture is allowed to stir for 1 h. Volatilesare removed in vacuo and the residue is partitioned between diluteaqueous base and ethyl acetate. Drying of the ethyl acetate extract andevaporation leads to the crude product which is optionally purified byflash chromatography on silica gel using 92.5:7:0.5chloroform:ethanol:ammonium hydroxide and crystallized from ethylacetate/hexane or converted to the HCl salt using dioxane/HCl followedby recrystallization from methanol/ether.

B) A stirred solution of 10 mmol acylating acid in 25 mL chloroform istreated with 10 mmol of triethylamine followed by 10 mmol of isobutylchloroformate. After 10 minutes at ambient temperature the amine ofExample 5 was added and the reaction is allowed to stir for 1/2 h. Thereaction mixture is washed with 10% NaOH solution and the organic layeris dried and evaporated to give a residue which is optionally purifiedby flash chromatography on silica gel using 92.5:7:0.5chloroform:ethanol:ammonium hydroxide recrystallized from ethyl acetateconverted to the HCl salt using dioxane/HCl followed byrecrystallization from methanol/ether.

EXAMPLE 7 Preparation of quaternary salt

A solution of 200 mg of the amide of Example 6 in 5 mL acetone wastreated with 4 drops of iodomethane. The reaction mixture was stirredfor 18 h and the white crystalline precipitate was filtered off toafford 206 mg of white solid which was recrystallized from acetonitrileto give 128 mg of quaternary iodide as fluffy white needles, mp236°-237° C.

EXAMPLE 8 Preparation of N-oxide

A solution of 0.50 g of the amide of Example 6 in 10 mL CH₂ Cl₂ wastreated with 300 mg of m-chloroperoxybenzoic acid at 0° C. After 1 h thesolution was washed consecutively with 10 mL 1N NaOH, water, and sat'd.brine. The solution was dried over sodium sulfate and concentrated toafford 0.51 g of white solid which was recrystallized from CH₂ Cl₂/ethyl acetate to give 0.33 g of an N-oxide as a white powder, mp200.5°-202.5° C.

EXAMPLE 9 THROUGH 89

Using the procedures of Examples 2 through 8 and making the appropriatesubstitutions at positions R₁, R₂, R₃, and X, the following productswere obtained as presented in Table I, below. Table I specifies themoiety at R₁, R₂, R₃ and ##STR10## the number of methylenes representedby n, the compound's melting point range in degrees Celsius (whereavailable) and the compound's elemental analysis. ##STR11## Allpiperidinyls are 4-piperidinyl unless otherwise noted.

      Example R.sup.1 R.sup.2 R.sup.3 X n mp, deg. C. Analysis      9     ##STR12##       H      ##STR13##      1  C.sub.18 H.sub.21 N.sub.3 O      10     ##STR14##       H      ##STR15##      1  C.sub.18 H.sub.21 N.sub.3 O      11     ##STR16##       H      ##STR17##      1  C.sub.18 H.sub.21 N.sub.3 O      12     ##STR18##       H      ##STR19##      1  C.sub.26 H.sub.33 ClN.sub.2 O.sub.2      13     ##STR20##       H      ##STR21##      1 155-157 C.sub.19 H.sub.28 N.sub.2 O      14     ##STR22##       H      ##STR23##      1   168-169.5 C.sub.19 H.sub.23 N.sub.3 O      15     ##STR24##       H      ##STR25##      1 155.5-158   C.sub.17 H.sub.20 N.sub.2 O.sub.2      16     ##STR26##       H      ##STR27##      1 170-171 C.sub.20 H.sub.30 N.sub.2 O.sub.2      17 CH.sub.3  H     ##STR28##      1 137-140 C.sub.15 H.sub.22 N.sub.2 O.sub.2      18     ##STR29##       H      ##STR30##      1 136-137 C.sub.18 H.sub.22 N.sub.2 O.sub.3      19     ##STR31##       H      ##STR32##      1 142-143 C.sub.23 H.sub.28 N.sub.2 O.sub.2      20     ##STR33##       H      ##STR34##      1 135-137 C.sub.22 H.sub. 26 N.sub.2 O.sub.2      21     ##STR35##       H      ##STR36##      1 136-138 C.sub.22 H.sub.24 N.sub.2 O.sub.3      22     ##STR37##       H      ##STR38##      1  C.sub.19 H.sub.23 N.sub.3 O.sub.2      23     ##STR39##       H      ##STR40##      1 161-162 C.sub.18 H.sub.22 N.sub.2 O.sub.2 S      24     ##STR41##       H      ##STR42##      1 200-202 C.sub.23 H.sub.24 N.sub.2 O.sub.4      25     ##STR43##       H      ##STR44##      1 210-211 C.sub.19 H.sub.24 N.sub.2 O.sub.2       26     ##STR45##       H      ##STR46##      1 134-137 C.sub.24 H.sub.32 N.sub.2 O.sub.4      27 CH.sub.3  H     ##STR47##      2 162-164 C.sub.16 H.sub.24 N.sub.2 O.sub.2      28     ##STR48##       H      ##STR49##      1 178.5-179.5 C.sub.18 H.sub.22 N.sub.2 O.sub.2      29     ##STR50##       H      ##STR51##      1 140-141 C.sub.22 H.sub.24 N.sub.2 O.sub.3      30     ##STR52##       H      ##STR53##      1 135-137 C.sub.23 H.sub.28 N.sub. 2 O.sub.2      31     ##STR54##       H      ##STR55##      1 156-158 C.sub.24 H.sub.30 N.sub.2 O.sub.2      32     ##STR56##       H      ##STR57##      1 122-124 C.sub.20 H.sub.26 N.sub.2 O.sub.3      33     ##STR58##       H      ##STR59##      1 132-134 C.sub.24 H.sub.28 N.sub.2 O.sub.3      34     ##STR60##       H      ##STR61##      1 148-149 C.sub.22 H.sub.23 ClN.sub.2 O.sub.3      35     ##STR62##       H      ##STR63##      1 156-158 C.sub.23 H.sub. 26 N.sub.2 O.sub.2      36     ##STR64##       H      ##STR65##      1 140-142 C.sub.23 H.sub.26 N.sub.2 O.sub.4.HCl      37     ##STR66##       H      ##STR67##      1 147-148 C.sub.24 H.sub.28 N.sub.2 O.sub.5      38     ##STR68##       H      ##STR69##      1 126-128 C.sub.22 H.sub.23 ClN.sub.2 O.sub.3      39     ##STR70##       H      ##STR71##      1 158-160 C.sub.22 H.sub.24 N.sub.2 O.sub.2 S      40     ##STR72##       H      ##STR73##      1 270-272 C.sub.23 H.sub.24 N.sub.2 O.sub.4.HCl      41     ##STR74##       H      ##STR75##      1 oil C.sub.22 H.sub.25 N.sub.2 O.sub.2.HCl      42     ##STR76##       H      ##STR77##      1 146-148 C.sub.23 H.sub.28 N.sub.2 O.sub.3      43     ##STR78##       H      ##STR79##      1 147-149 C.sub.23 H.sub.28 N.sub.2 O.sub.3      44     ##STR80##       H      ##STR81##      1 145-147 C.sub.20 H.sub.25 N.sub.3 O.sub.2      45     ##STR82##       H      ##STR83##      1 150-152 C.sub.21 H.sub.25 N.sub.3 O.sub.2      46     ##STR84##       H      ##STR85##      1 142-144 C.sub.23 H.sub.26 N.sub.2 O.sub.3      47     ##STR86##       H      ##STR87##      1 131-133 C.sub.22 H.sub.28 N.sub.2 O.sub.2      48     ##STR88##       H      ##STR89##      1 141-143 C.sub.23 H.sub.28 N.sub.2 O.sub.2      49     ##STR90##       H      ##STR91##      1 125-127 C.sub.23 H.sub.30 N.sub.2 O.sub.2.HCl      50     ##STR92##       H      ##STR93##      1 92-96 C.sub.23 H.sub.28 N.sub.2 O.sub.2.HCl      51     ##STR94##       H      ##STR95##      1 134.5-135   C.sub.22 H.sub.26 N.sub.2 O.sub.3      52     ##STR96##       H      ##STR97##      1  C.sub.21 H.sub.26 N.sub.2 O.sub.2      53     ##STR98##       H      ##STR99##      1 190-192 C.sub.22 H.sub.23 N.sub.3 O.sub.5      54     ##STR100##       H      ##STR101##      1 197-199 C.sub.22 H.sub.25 N.sub.3 O.sub.4      55     ##STR102##       H      ##STR103##      1  C.sub.17 H.sub.24 N.sub. 2 O.sub.2      56     ##STR104##       H      ##STR105##      1 210-212 C.sub.22 H.sub.24 Cl.sub.2 N.sub.2 O.sub.2      57     ##STR106##       H      ##STR107##      1 142-143 C.sub.24 H.sub.30 N.sub.2 O.sub.2      58     ##STR108##       H      ##STR109##      1 133-135 C.sub.18 H.sub.21 BrN.sub.2 O.sub.3      59     ##STR110##       H      ##STR111##      1 155-157 C.sub.21 H.sub.22 N.sub.2 O.sub.3      60     ##STR112##       H      ##STR113##      1 215-218 C.sub.23 H.sub.29 N.sub.3 O.sub.4 S       61 CH.sub.3  H     ##STR114##      1 143-144 C.sub.14 H.sub.19 N.sub.3 O.sub.3      62     ##STR115##       H      ##STR116##      1 155-157 C.sub.21 H.sub.21 N.sub.3 O.sub.4      63 CH.sub.3  H     ##STR117##      1 162-164 C.sub.14 H.sub.19 ClN.sub.2 O      64     ##STR118##       H      ##STR119##      1 137-139 C.sub.21 H.sub.21 ClN.sub.2 O.sub.2      65     ##STR120##       H      ##STR121##      1 157-159 C.sub.24 H.sub.30 N.sub.2 O.sub.2      66     ##STR122##      CH.sub.3 H      ##STR123##      1 236-237 C.sub.23 H.sub.26 N.sub. 2 O.sub.3.Hl      67     ##STR124##       H      ##STR125##      1   184-185.5 C.sub.21 H.sub.28 N.sub.2 O.sub.2  68 CH.sub.3  H      ##STR126##      1   163-164.5 C.sub.13 H.sub.19 N.sub.3 O      69 CH.sub.3  H     ##STR127##      1 103-105 C.sub.15 H.sub.22 N.sub.2 O.sub.2      70     ##STR128##       H      ##STR129##      1 114-115 C.sub.22 H.sub.24 N.sub.2 O.sub.3      71 CH.sub.3  H     ##STR130##      1  C.sub.15 H.sub.22 N.sub.2 O.sub.2      72     ##STR131##      O H      ##STR132##      1 200.5-202.5 C.sub.22 H.sub.24 N.sub.2 O.sub.4      73     ##STR133##       H H 1  C.sub.15 H.sub.18 N.sub.2 O.sub.2      74 CH.sub.3  H     ##STR134##      1 145-147 C.sub.16 H.sub.23 N.sub.3 O.sub.2.CHOOOH      75     ##STR135##       H      ##STR136##      1 230-232 C.sub.23 H.sub.25 N.sub.3 O.sub.3      76     ##STR137##       H      ##STR138##      1  C.sub.22 H.sub.25 ClN.sub.2 O.sub.3      77     ##STR139##       H      ##STR140##      1  C.sub.23 H.sub.26 N.sub.2 O.sub.4      78     ##STR141##       H      ##STR142##      1  C.sub.23 H.sub.27 N.sub.3 O.sub.2.2(HCl)      79     ##STR143##       H      ##STR144##      1 189-190 C.sub.22 H.sub.23 N.sub.3 O.sub.5      80     ##STR145##       H      ##STR146##      1  98-100 C.sub.22 H.sub.27 N.sub.3 O.sub.3.2(HCl)  81 CH.sub.3  H      ##STR147##      1(substituted byCO.sub.2 CH.sub.2 CH.sub.3)  C.sub.17 H.sub.24 N.sub.2     O.sub.3      82     ##STR148##       CH.sub.2 CO.sub.2 CH.sub.2      CH.sub.3     ##STR149##      1  C.sub.26 H.sub.31 ClN.sub.2 O.sub.5      83     ##STR150##       CH.sub.2 CO.sub.2      H     ##STR151##      1  C.sub.24 H.sub.26 N.sub.2 O.sub.5      84     ##STR152##       H      ##STR153##      1 152-153 C.sub.24 H.sub.30 N.sub.2 O.sub.2      85     ##STR154##       H      ##STR155##      1 198-200 C.sub.21 H.sub.22 N.sub.2 O.sub.3      86 CH.sub.3  H     ##STR156##      1  C.sub.12 H.sub.18 N.sub.2 O.sub.2      87     ##STR157##       H      ##STR158##      1  C.sub.23 H.sub.28 N.sub.2 O.sub.2      88     ##STR159##       H      ##STR160##      1  C.sub.20 H.sub.22 N.sub. 2 OF.sub.3      89     ##STR161##       H      ##STR162##      1  C.sub.21 H.sub.27 N.sub.2      O.sub.3

While the invention has been described and illustrated with reference tocertain preparative embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred rangeas set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of cardiac arrhythmia, dosage-related adverse effects, if any,and analogous considerations. Likewise, the specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentcertain pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations fordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow, and that such claims be interpreted as broadly as isreasonable.

What is claimed is:
 1. A compound of the formula ##STR163## or thepharmaceutically acceptable non-toxic salts thereof, or the hydratedforms thereof, wherein R¹ is alkenyl or alkynyl of from two to tencarbon atoms; substituted or unsubstituted phenylalkenyl orphenylalkynyl of from two to ten carbon atoms and wherein said phenylsubstituent is one or more of alkoxy, nitro, halogen or alkylsulfonamideat any position with alkoxy or alkylsulfonamide of one to ten carbonatoms; unsubstituted phenyl which is fused to substituted orunsubstituted cycloalkyl of from three to eight carbon atoms whereinsaid cycloalkyl substituent can be halogen; phenylamino;phenylcycloalkyl wherein cycloalkyl is from three to eight carbon atoms;furanyl alkenyl wherein the alkenyl portion is from two to eight carbonatoms; substituted or unsubstituted benzofuranyl wherein saidbenzofuranyl substituent can be one or more of halogen, amino, nitro oralkoxy of from one to ten carbon atoms at any position; substituted orunsubstituted benzopyran wherein said substituent can be keto;thiophene; benzothiophene; or substituted or unsubstituted indene orisoindene wherein said substituent is alkyl of one to ten carbon atoms;nis an integer of from one to ten; R² is alkyl of from one to ten carbonatoms, oxygen that is present as an N-oxide or absent; R³ is hydrogen,carboxyalkyl of from one to ten carbon atoms or alkoxycarbonylalkyl offrom one to ten carbon atoms; ##STR164## is hydrogen; pyridinyl;cycloalkyl of three to eight carbon atoms or hydroxy substitutedcycloalkyl of three to eight carbon atoms; furanyl; or unsubstituted orsubstituted phenyl wherein said phenyl substituent is one or more ofalkyl or halogen substituted alkyl of one to ten carbon atoms, alkoxyfrom one to ten carbon atoms, nitro, amine, mono or dialkylamine, acetylamine, acetylamide, halogen, hydroxy or alkoxy itself substituted byhalogen substituted phenyl.
 2. The compound as claimed in claim 1,wherein R¹ is --CH═CH--CH₃.
 3. The compound as claimed in claim 1,wherein R¹ is ##STR165##
 4. The compound as claimed in claim 1, whereinR¹ is ##STR166##
 5. The compound as claimed in claim 1, wherein R¹ is##STR167##
 6. The compound as claimed in claim 1, wherein R¹ is##STR168##
 7. The compound as claimed in claim 1, wherein R¹ is##STR169##
 8. The compound as claimed in claim 1, wherein R¹ is##STR170##
 9. The compound as claimed in claim 1, wherein R¹ is##STR171##
 10. The compound as claimed in claim 1, wherein R¹ is##STR172##
 11. The compound as claimed in claim 1, wherein R¹ is##STR173##
 12. The compound as claimed in claim 1, wherein R¹ is##STR174##
 13. The compound as claimed in claim 1, wherein R¹ is##STR175##
 14. The compound as claimed in claim 1, wherein R¹ is##STR176##
 15. The compound as claimed in claim 1, wherein R¹ is##STR177##
 16. The compound as claimed in claim 1, wherein R¹ is##STR178##
 17. The compound as claimed in claim 1, wherein R¹ is##STR179##
 18. The compound as claimed in claim 1, wherein R¹ is##STR180##
 19. The compound as claimed in claim 1, wherein R¹ is##STR181##
 20. The compound as claimed in claim 1, wherein R¹ is##STR182##
 21. The compound as claimed in claim 1, wherein R¹ is##STR183##
 22. The compound as claimed in claim 1, wherein R¹ is##STR184##
 23. The compound as claimed in claim 1, wherein R¹ is##STR185##
 24. The compound as claimed in claim 1, wherein R¹ is##STR186##
 25. The compound as claimed in claim 1, wherein R¹ is##STR187##
 26. The compound as claimed in claim 1, wherein R¹ is##STR188##
 27. The compound as claimed in claim 1, wherein R¹ is##STR189##
 28. The compound as claimed in claim 1, wherein R¹ is##STR190##
 29. The compound as claimed in claim 1, wherein n is
 1. 30.The compound as claimed in claim 1, wherein n is
 2. 31. The compound asclaimed in claim 1, wherein R² is --CH₃.
 32. The compound as claimed inclaim 1, wherein R² is oxygen, present as an N-oxide.
 33. The compoundas claimed in claim 1, wherein ##STR191## is hydrogen.
 34. The compoundas claimed in claim 1, wherein ##STR192##
 35. The compound as claimed inclaim 1, wherein ##STR193##
 36. The compound as claimed in claim 1,wherein ##STR194##
 37. The compound as claimed in claim 1, wherein##STR195##
 38. The compound as claimed in claim 1, wherein ##STR196##39. The compound as claimed in claim 1, wherein ##STR197##
 40. Thecompound as claimed in claim 1, wherein ##STR198##
 41. The compound asclaimed in claim 1, wherein ##STR199##
 42. The compound as claimed inclaim 1, wherein ##STR200##
 43. The compound as claimed in claim 1,wherein ##STR201##
 44. The compound as claimed in claim 1, wherein##STR202##
 45. The compound as claimed in claim 1, wherein ##STR203##46. The compound as claimed in claim 1, wherein ##STR204##
 47. Thecompound as claimed in claim 1, wherein R³ is ##STR205##
 48. Thecompound as claimed in claim 1, wherein R³ is ##STR206##
 49. A compoundas claimed in claim 1, of the formula ##STR207##
 50. A compound asclaimed in claim 1, of the formula ##STR208##
 51. A compound as claimedin claim 1, of the formula ##STR209##
 52. A compound as claimed in claim1, of the formula ##STR210##
 53. A compound as claimed in claim 1, ofthe formula ##STR211##
 54. A compound as claimed in claim 1, of theformula ##STR212##
 55. A compound as claimed in claim 1, of the formula##STR213##
 56. A compound as claimed in claim 1, of the formula##STR214##
 57. A compound as claimed in claim 1, of the formula##STR215##
 58. A compound as claimed in claim 1, of the formula##STR216##
 59. A compound as claimed in claim 1, of the formula##STR217##
 60. A compound as claimed in claim 1, of the formula##STR218##
 61. A compound as claimed in claim 1, of the formula##STR219##
 62. A compound as claimed in claim 1, of the formula##STR220##
 63. A compound as claimed in claim 1, of the formula##STR221##
 64. A compound as claimed in claim 1, of the formula##STR222##
 65. A compound as claimed in claim 1, of the formula##STR223##
 66. A compound as claimed in claim 1, of the formula##STR224##
 67. A compound as claimed in claim 1, of the formula##STR225##
 68. A compound as claimed in claim 1, of the formula##STR226##
 69. A compound as claimed in claim 1, of the formula##STR227##
 70. A compound as claimed in claim 1, of the formula##STR228##
 71. A compound as claimed in claim 1, of the formula##STR229##
 72. A compound as claimed in claim 1, of the formula##STR230##
 73. A compound as claimed in claim 1, of the formula##STR231##
 74. A compound as claimed in claim 1, of the formula##STR232##
 75. A compound as claimed in claim 1, of the formula##STR233##
 76. A compound as claimed in claim 1, of the formula##STR234##
 77. A compound as claimed in claim 1, of the formula##STR235##
 78. A compound as claimed in claim 1, of the formula##STR236##
 79. A compound as claimed in claim 1, of the formula##STR237##
 80. A compound as claimed in claim 1, of the formula##STR238##
 81. A compound as claimed in claim 1, of the formula##STR239##
 82. A compound as claimed in claim 1, of the formula##STR240##
 83. A compound as claimed in claim 1, of the formula##STR241##
 84. A compound as claimed in claim 1, of the formula##STR242##
 85. A compound as claimed in claim 1, of the formula##STR243##
 86. A compound as claimed in claim 1, of the formula##STR244##
 87. A compound as claimed in claim 1, of the formula##STR245##
 88. A compound as claimed in claim 1, of the formula##STR246##
 89. A compound as claimed in claim 1, of the formula##STR247##
 90. A compound as claimed in claim 1, of the formula##STR248##
 91. A compound as claimed in claim 1, of the formula##STR249##
 92. A compound as claimed in claim 1, of the formula##STR250##
 93. A compound as claimed in claim 1, of the formula##STR251##
 94. A compound as claimed in claim 1, of the formula##STR252##
 95. A compound as claimed in claim 1, of the formula##STR253##
 96. A compound as claimed in claim 1, of the formula##STR254##
 97. A pharmaceutical composition useful for regulatingcardiac arrhythmias comprising an effective amount of a compoundaccording to claim 1, together with one or more non-toxicpharmaceutically acceptable carriers.
 98. The composition as claimed inclaim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl-2E-butenamide.
 99. Thecomposition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-phenyl-2E-propenamide.100. The composition as claimed in claim 97, wherein said compound is3-phenyl-N-[1-[(propoxyphenyl)methyl]-4-piperidinyl]-2E-propenamide.101. The composition as claimed in claim 97, wherein said compound is3-(2-methoxyphenyl)-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2E-propenamide.102. The composition as claimed in claim 97, wherein said compound is3-(2-methoxyphenyl)-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2Z-propenamide,monohydrochloride.
 103. The composition as claimed in claim 97, whereinsaid compound is3-(4-methoxyphenyl)-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2E-propenamide.104. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-(4-nitrophenyl)-2E-propenamide.105. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-[4-(methylsulfonyl)amino]phenyl]-2E-propenamide.106. The composition as claimed in claim 97, wherein said compound is3-(2,6-dichlorophenyl)-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2E-propenamide.107. The composition as claimed in claim 97, wherein said compound is3-(2-furanyl)-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2E-propenamide108. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-phenyl-2-propynamide,monohydrochloride.
 109. The composition as claimed in claim 97, whereinsaid compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-phenylcyclopropanecarboxamide.110. The composition as claimed in claim 97, wherein said compound is2,3-dihydro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1H-indene-1-carboxamide.111. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-methyl-1H-indene-2-carboxamide.112. The composition as claimed in claim 97, wherein said compound is(-)1,2,3,4-tetrahydro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-naphthalenecarboxamide.113. The composition as claimed in claim 97, wherein said compound is(+)1,2,3,4-tetrahydro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-naphthalenecarboxamide.114. The composition as claimed in claim 97, wherein said compound is2,3-dihydro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.115. The composition as claimed in claim 97, wherein said compound isN-(1-methyl-4-piperidinyl)-2-benzofurancarboxamide.
 116. The compositionas claimed in claim 97, wherein said compound isN-[1-(cyclohexylmethyl)-4-piperidinyl]-2-benzofuracarboxamide.
 117. Thecomposition as claimed in claim 97, wherein said compound isN-[1-(phenylmethyl)-4-piperidinyl]-2-benzofurancarboxamide.
 118. Thecomposition as claimed in claim 97, wherein said compound isN-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.119. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-hydroxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.120. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.121. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-benzofurancarboxamide.122. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-3-piperidinyl]-2-benzofurancarboxamide.123. The composition as claimed in claim 97, wherein said compound is4-[(2-benzofuranylcarbonyl)amino]-1-[(4-methoxyphenyl)methyl]-1-methylpiperidiniumiodide.
 124. The composition as claimed in claim 97, wherein saidcompound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide,N-oxide.
 125. The composition as claimed in claim 97, wherein saidcompound isN-[1-[(4-propoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.126. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-nitrophenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.127. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-(acetylamino)phenylmethyl]-4-piperidinyl]-2-benzofurancarboxamide.128. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-methyl-2-benzofurancarboxamide.129. The composition as claimed in claim 97, wherein said compound is7-chloro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.130. The composition as claimed in claim 97, wherein said compound is5-chloro-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.131. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-5-nitro-2-benzofurancarboxamide.132. The composition as claimed in claim 97, wherein said compound is7-methoxy-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide,monohydrochloride.
 133. The composition as claimed in claim 97, whereinsaid compound is6,7-dimethoxy-N-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzofurancarboxamide.134. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-oxo-2H-1-benzopyran-3-carboxamide.135. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-4-oxo-4H-1-benzopyran-3-carboxamide,monohydrochloride.
 136. The composition as claimed in claim 97, whereinsaid compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-thiophenecarboxamide.137. The composition as claimed in claim 97, wherein said compound isN-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-2-benzo[b]thiophenecarboxamide.138. A method of regulating cardiac arrhythmias in a mammal, comprisingadministering to said mammal a pharmacologically effective amount of acompound as claimed in claim
 1. 139. A method of prolongingrepolarization of cardiac cells during a cardiac action potential,comprising administering to said mammal a pharmacologically effectiveamount of a compound as claimed in claim 1.